The present invention relates to xcex1-azacyclomethylquinoline derivatives, to their preparation and to their therapeutic application.
The compounds correspond to the general formula (I): 
in which:
A represents either a hydrogen atom or a hydroxyl group,
B represents a 2-pyrrolidinyl (D) or 2-piperidyl (E), 
R1 represents a hydrogen atom, a C1-6 alkyl, C2-6 alkenyl, C1-2 perfluoroalkyl or C1-6 fluoroalkyl group,
R2, R3 or R4 represent, independently of each other, a hydrogen atom, a C1-6 alkyl group or a C2-6 alkenyl group, or
R1 and R2 together may also form a C1-6 alkylene chain or a C3-6 alkenylene chain,
R5 represents a C1-6 alkyl group,
R6 represents a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C3-6 cycloalkyl group, a C3-6 cycloalkenyl group or a benzyl, and
xe2x80x9cnxe2x80x9d represents 0, 1 or 2.
More particularly, the compounds for which A represents a hydroxyl group are preferred.
Moreover, the compounds for which R1 represents a C1-6 alkyl group, preferably C1-3 alkyl and more particularly an ethyl, are found to be advantageous.
Other preferred compounds are the compounds for which R2 and R3 represent, independently of each other, a hydrogen atom or a C1-3 alkyl group, more particularly a methyl.
The compounds for which A, R1, R2 and R3 are as defined in the groups of preferred compounds are most particularly preferred.
In the context of the present invention, the term xe2x80x9cC1-6 alkylxe2x80x9d means a saturated, linear or branched aliphatic group comprising from 1 to 6 carbon atoms, such as, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc. group. The term xe2x80x9cC1-6 alkylenexe2x80x9d denotes a divalent C1-6 alkyl group.
The term xe2x80x9cC2-6 alkenylxe2x80x9d denotes a monounsaturated or polyunsaturated, linear or branched aliphatic group comprising from 2 to 6 carbon atoms. According to the invention, an alkenyl group preferably comprises 1 or 2 ethylenic unsaturations. The term xe2x80x9cC2-6 alkenylenexe2x80x9d denotes a divalent C2-6 alkenyl group.
The term xe2x80x9cC3-6 cycloalkylxe2x80x9d denotes a saturated cyclic aliphatic system comprising from 3 to 6 carbon atoms.
The term xe2x80x9cC3-6 cycloalkenylxe2x80x9d denotes a unsaturated cyclic aliphatic system comprising from 3 to 6 carbon atoms. According to the invention, a C3-6 cycloalkenyl group preferably comprises 1 or 2 unsaturations.
The term xe2x80x9cprotecting group Pgxe2x80x9d means a group which firstly protect a reactive function such as a hydroxyl or an amine during a synthesis, and secondly allows the reactive function to be regenerated intact at the end of the synthesis. Examples of protecting groups and protection and deprotection methods are given in Protective group in Organic Synthesis Greene et al., 2nd Ed. (John Wiley and Sons, Inc., New York).
Moreover, in the schemes, xe2x97xaf represents a solid support.
A solid support consists of an insoluble material bearing functionalization intended to capture a chemical compound.
Examples of such materials are polymers, plastics, resins, polysaccharides and silica derivatives. Preferably, resins are used, and more preferably polystyrene resins or resins of mixed polystyrene/ethylene glycol (PS-PEG) type.
Functionalization depends on the molecule to be captured. For example, this functionalization may consist of a halo, hydroxyl, aldehyde, carboxyl, amino, trityl or thiol group.
Such solid supports comprising suitable functionalization or which require a preactivation by methods known to those skilled in the art are commercially available in particular from Novabiochem, Rapp Polymer, Sigma, Aldrich, Polymer Laboratories or Argonaut Technologies.
Preferably, the solid support is a carboxy resin activated as acid chloride or a trityl chloride resin or an Elleman dihydropyran resin.
The compounds of general formula (I) may comprise one or more asymmetric carbon atoms. They may thus exist in the form of enantiomers or diastereoisomers. These enantiomers and diastereoisomers, and the mixtures thereof including racemic mixtures, form part of the invention.
The compounds of general formula (I) may be in the form of free base or of addition salts with acids, which also form part of the invention. According to the present invention, these salts comprise those with mineral or organic acids which allow a suitable separation or crystallization of the compounds of formula (I), such as picric acid, oxalic acid or an optically active acid, for example a tartaric acid, a dibenzoyltartaric acid, a mandelic acid or a camphorsulfonic acid, and those which form physiologically acceptable salts, such as the hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, maleate, fumarate, citrate, pamoate, 2-naphthalenesulfonate or paratoluenesulfonate. Although the pharmaceutically acceptable salts are preferred, the other salts form part of the present invention. These salts may be prepared according to methods known to those skilled in the art, for example by reacting the compound of formula (I) in base form with the acid in a suitable solvent, such as an alcoholic solution or an organic solvent, followed by separation from the medium containing them by evaporation of the solvent or by filtration.
The compounds derived from xcex1-azacyclomethylquinoline of formula (I) according to the invention may be prepared according to different processes. The compounds of formula (I), in particular those for which A represents a hydroxyl group, may be prepared according to the process described in Scheme 1.
According to this process, the compounds of formula (I) for which R6 represents a hydrogen atom are obtained by cleaving from the solid support the compounds of formula (II) derived from the deprotection of the protecting group Pg on the nitrogen of the compound of formula (III), according to methods known to those skilled in the art. Such a protecting group may be, for example, a C1-6 alkoxycarbonyl group such as tert-butyloxycarbonyl (tBoc). The meanings of R1, R2, R3, R4, R5 and n in the compounds of formulae (II) and (III), are those given in formula (I).
The secondary amine in the compounds of formula (II) thus obtained may then be functionalized, according to processes known to those skilled in the art, for example by reductive amination (under the conditions described by Balasubranian et al., Tetrahedron Letters, vol. 37, No. 27, pp. 4819-4822) to give, after cleavage from the solid support, a compound of formula (I) in which R6 is not a hydrogen.
The compounds of formula (III) may be obtained by uptake using an activated solid support of the reaction mixture derived from the reaction of an aldehyde of formula (VIII), in which Pg represents a protecting group known to those skilled in the art, with a derivative (IV) obtained by metallation of the halo derivative of formula (V). The meanings of R1, R2, R3, R4, R5, B and n in the compounds of formulae (V) (IV) and (VIII) are those given in formula (I). The metallation reaction may be carried out in an organic solvent such as tetrahydrofuran, by forming the Grignard reagent of the halo derivative of formula (V), in which Y represents a halogen, or more advantageously by reacting the halo derivative of formula (V) in the presence of n-butyllithium preferably at temperatures of about xe2x88x9278xc2x0 C. The term xe2x80x9cmetalxe2x80x9d in formula (IV) represents, for example, lithium Li. 
The aldehydes of formula (VIII) may be obtained by reduction, for example according to the method described by Jurczack J. et al., Chem. Rev (1989), 89, 149, starting with the corresponding N-protected xcex1-amino acid derivatives of formula (IX) which are themselves derived from the xcex1-amino acids of formula (X). R5, B and n have the meanings given in formula (I). Pg is defined as above and Z represents a group, which is known to those skilled in the art, allowing controlled reduction which stops at the formation of an aldehyde, inter alia, N-methyl-O-methylhydroxylamine (Nahm and Weinreb (1981), Tet., Lett., 22, 3815).
The compounds of formula (V) may themselves be prepared either by a Skraup or Doebner-Miller reaction. According to this process and under the conditions defined by Belser P. Tetrahedron 1996, Vol 52, No. 8, 2937-2944 or advantageously under the conditions defined by Z. Song J. Heterocyclic Chem. 1993, 30, 17-21, an aniline of formula (VII), for which Y represents a halogen such as a bromine or an iodine, and an xcex1,xcex2-unsaturated aldehyde or ketone of formula (VI) are heated in the presence of a dehydrating agent such as sulfuric acid and an oxidizing agent such as sodium iodide, to form a quinoline derivative substituted in position 8 with Y. The meanings of R1, R2, R3 and R4 in the compounds of formulae (V), (VI) and (VII) are those given in formula (I).
Alternatively, the compounds of formula (I) in which A represents a hydroxyl group may be prepared without using the resin, by keeping the hydroxyl group free.
The compounds of formula (I) according to the invention, for which A is a hydrogen atom, may be prepared by dehydroxylation of a corresponding compound of formula (I) in which A is a hydroxyl group.
The dehydroxylation reaction may be carried out, in a manner which is known to those skilled in the art, by reaction with triethylsilane and trifluoroacetic acid or according to the process described by Myers, A. G.; Movassaghi, M.; Zheng, B. J. Am. Chem. Soc. 1997, 119, 8572-8573.
The starting compounds, in particular those of formulae VII and VI, are commercially available or may be prepared according to methods known to those skilled in the art.